We are investigating how heparan sulfate influences FGFR2b signaling in specific progenitor cell types in the epithelium. The exquisite control of growth factor function by HS is dictated by the tremendous structural heterogeneity of its sulfated modifications. It is not known how specific HS structures control growth factor-dependent progenitor expansion during organogenesis. We isolated KIT+ progenitors from fetal salivary glands during a stage of rapid progenitor expansion and profiled HS biosynthetic enzyme expression. Enzymes generating a specific type of 3-O-sulfated-HS (3-O-HS) are enriched in the KIT+ cells, and FGF10/FGFR2b signaling directly regulates their expression. We used bioengineered 3-O-HS to investigate HS function. 3-O-HS binds FGFR2b and stabilizes FGF10/FGFR2b complexes in a receptor- and growth factor-specific manner. Rapid autocrine feedback increases 3-O-HS, KIT and progenitor expansion. In complementary experiments, the knockdown of multiple Hs3st isoforms limits fetal progenitor expansion, but is rescued with bioengineered 3-O-HS, which also increases adult progenitor expansion. We show that rapidly altering a specific 3-O-sulfated epitope provides a cellular mechanism to modulate the response to FGFR2b signaling and control progenitor expansion. We propose that 3-O-HS may expand KIT+ progenitors isolated from biopsies in vitro to use for salivary gland regeneration. We are also identifying the signals that initiate ganglion formation in the salivary gland. Nerves often follow alongside blood vessels to navigate to their targets using similar sets of guidance cues. However, defining the signals that initiate the association between the peripheral nervous system and the salivary epithelium will be important to regenerate or engineer functioning organs. During SMG organogenesis innervation begins when neural crest-derived Schwan cell precursors differentiate into neurons and condense around the epithelial duct to form the parasympathetic ganglion. Subsequently the ganglion neurons extend axons to innervate the epithelium of the gland. We are studying epithelial-derived factors that initiate the neuronal-epithelial communication resulting in neurons condensing around the duct. These epithelial signals are dependent on the localized repression of FGF signaling within the duct. In contrast, enhanced epithelial FGF signaling antagonizes these factors, resulting in defects in epithelial-neuronal communication leading to disrupted ganglia formation and epithelial morphology. This also results in a subsequent depletion of the epithelial progenitor cell reservoir. Our studies demonstrate that epithelial-derived factors are required for gangliogenesis and association with the epithelial duct. Signals that promote gangliogenesis and neuronal-epithelial interactions may inform organ engineering, regeneration, and repair.